The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the PKA holoenzyme to discrete locations within the cell. There are at least 50 different AKAPs, all of which have been cloned. Typical AKAPs include for example AKAP79, AKAP18, AKAP450, all of which are somewhat arbitrarily named after their apparent mobility by SDS-poly acrylamide gel electrophoresis. Later, the gene nomenclature committee has also introduced a separate nomenclature for AKAPs where they are consecutively numbered AKAP1, AKAP2, AKAP3 etc. In addition, some AKAPs like ezrin and Opa1 have already been assigned other names that are in use.
KAPs act as targeting devices that assemble signaling elements on a scaffold (the AKAP) that itself targets to microdomains in cells. This allows specific targeting of substrates to be regulated by phosphorylation (by PKA) and dephosphorylation (by phosphatases). PKA binds via its regulatory subunits (RIα, RIIα, RIβ, RIIβ) directly to an amphipathic α-helix in the AKAP, which is a common feature of AKAPs. The AKAPs also bind other components including; phosphodiesterases (PDEs) which break down cAMP, phosphatases which dephosphorylate downstream PKA targets and also other kinases (PKC and MAPK). Some AKAPs are able to bind both regulatory subunits (RI & RII) of PKA and are dual-specific AKAPs (for example D-AKAP1, D-AKAP2, ezrin, OPA1).
For references related the various AKAPs and their biological functions see for example:
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There are a so far only a limited number of patent documents describing AKAPs. The most relevant documents are:
US2011/158905 (IBC Pharmaceuticals) describes a fusion protein comprising an 20 Nov. 2013 anchoring domain (AD) moiety or a dimerization and docking domain (DDD) moiety, wherein the AD moiety consists of the amino acid sequence of the AD moiety of an AKAP (A-kinase anchoring protein) and the DDD moiety consists of the amino acid sequence of the DDD moiety of a human protein kinase A regulatory subunit; and an effector moiety. The effector moiety is selected from the group consisting of an antibody, an antigen-binding antibody fragment, a cytokine, a viral antigen, a xenoantigen, an RNase, a heat shock protein, the N-A1 domain of CEACAM5, the A3-B3 domain of CEACAM5, alpha2-macroglobulin, HSA (human serum albumin), a human protamine, and Fc fragment of a human antibody and a nucleic acid binding protein. The proteins might be useful for treatment of various diseases or conditions selected from the group consisting of cancer, autoimmune disease, immune dysregulation disease, organ-graft rejection, graft-versus-host disease, a neurodegenerative disease, a metabolic disease and a cardiovascular disease.
U.S. Pat. No. 7,432,342 (Sequenom) relates to A-kinase anchor protein (AKAPs) muteins, peptides thereof, and nucleic acids encoding the peptides, especially a polypeptide that is a mutein of a D-AKAP2 polypeptide, wherein the mutein exhibits modified binding to a regulatory subunit of PKA compared to a native D-AKAP2.
EP2098226 (Forsungsverbund Berlin E.V.) describes use of bicyclic compounds (I) or their salts, solvates, hydrates or formulations for preparing a medicament for the prophylaxis or treatment of diseases associated with defect of compartmentalized cyclic adenosine monophosphate (cAMP)-dependent signal transduction, is claimed. Use of bicyclic compounds of formula (I) or their salts, solvates, hydrates or formulations for preparing a medicament for the prophylaxis or treatment of diseases associated with defect of compartmentalized cyclic adenosine monophosphate (cAMP)-dependent signal transduction, is claimed. Formula (X) describes a general bicyclic formula in EP2098226, while formula (I) describes biphenyl compounds which are the most preferred compounds.

A: O, S, NH, CO, (hetero)alkyl, alkenyl, alkynyl, (hetero)aryl, cycloalkylene, (hetero)alkylcycloalkylene, heterocycloalkylene or (hetero)aralkylene group; R, R1: H, halo, NH2, OH, NO2, (hetero)alkyl, alkenyl, alkynyl (all preferred), SH, N3, (hetero)aryl, (hetero)cycloalkyl, (hetero)alkylcycloalkyl or (hetero)aralkyl residue; D, E: (hetero)aryl, (hetero)cycloalkyl, (hetero)alkylcycloalkyl or (hetero)aralkyl (preferably substituted phenyl group); and m, n: 0-5 (preferably 1-3). The mechanism of action for these bicyclic compounds are protein kinease A and as AKAP interaction inhibitor. The indications for these agents are cardiovascular indications like hypertension and vasotropic activity.
WO2007/028969 (University of Oslo) relates to molecules which modify the binding between AKAP 18d and phosphodiesterase 4D or AKAP 18d and phospholamban and their use in altering PKA type II-mediated, activation of SERCA2 in a cell, for example to alleviate cardiovascular disease. Preferably such molecules include the motif RRASTIE. Molecules such as those which mimic binding of AKAP 18d to PKA, which allow enhanced phosphorylation of PLB are also discussed. No low-molecular weight compounds are specifically mentioned in this document.
WO2006/122546 describes non-peptide protein kinase A/protein kinase A anchor protein decouplers or disruptors. The compounds are listed in extensive tables of compounds. The chemical structures are structurally diverse and cannot be represented in any general formula. The compounds disclosed in these tables do not fall within the general formula of compounds of the present invention. The potential indications for use of these compounds are very broad including an extensive listing of very many different diseases, disorders and conditions.
WO2006/154330 (Forsungsverbund Berlin E.V.) relates to a nucleic acid sequence encoding a protein kinase A anchor protein, to the use of said nucleic acid sequence in a fusion protein, to a method of determining the interaction of said protein kinase A anchor protein with regulatory subunits of protein kinase A, and to a method of identifying cell-permeable substances.
WO2006/032923 (University of Oslo) describes a PKA I anchoring disrupting molecule or AKAP mimic, wherein said molecule or mimic is a polypeptide which comprises the following amino acid sequence: X1 X2 X3 Y A X4 X5 L A X6 X7 X8 I X9 X10 X11 X12 X13 (sequence (1)) or a peptidomimetic or analogue thereof is provided. Also provided are antibodies to the molecule, nucleic acid molecules comprising a sequence encoding the molecule and pharmaceutical compositions. A method of altering the PKA type I signaling pathway in a cell by administration of the anchoring disruption molecule or AKAP mimic, in particular to treat immunosuppressive disorders, proliferative diseases or autoimmune diseases is also described.
WO2006/032909 (University of Oslo) describes a PKA II anchoring disruption molecule or AKAP mimic, wherein said molecule or mimic is a polypeptide which comprises the following amino acid sequence: X1 X2 E X3 X4 A K Q I V X5 X6 X7 I X8 X9 X10 (sequence (1)) or a peptidomimetic or analogue thereof is provided. Also provided are antibodies to the molecule, nucleic acid molecules comprising a sequence encoding the molecule and pharmaceutical compositions. A method of altering the PKA type II signaling pathway in a cell by administration of the anchoring disruption molecule or AKAP mimic, in particular to treat cardiovascular and metabolic disorders is also described.
US2009/104177 (Forsungsverbund Berlin E.V.) relates to a nucleic acid sequence encoding peptides which inhibit the interaction of protein kinase A (PKA) and protein kinase A anchor proteins (AKAP), to a host organism comprising said nucleic acid sequence and optionally expressing said peptides, to the use of said peptides and of said host organism in investigating diseases associated with said AKAP-PKA interaction, and to the use of said peptides as pharmaceutical agent for the treatment of such diseases.
U.S. Pat. No. 6,958,214 (Sequenom) relates to polymorphic A-kinase anchor proteins (AKAPs) and nucleic acids encoding the proteins are provided herein. Methods of detecting polymorphic AKAPs and nucleic acids encoding the AKAPs, and kits for use in the detection methods are also provided. Further provided herein are methods of identifying subjects having or at risk of developing disorders of signal transduction. Methods of determining susceptibility to morbidity and/or increased or early mortality are also described.
WO2004/081576 (Sequenom) relates to polymorphic A-kinase anchor proteins (AKAPs) and nucleic acids encoding the proteins are provided herein. Methods of detecting polymorphic AKAPs and nucleic acids encoding the AKAPs, and kits for use in the detection methods are also provided. Further provided herein are methods of identifying subjects having or at risk of developing diseases or disorders, such as those related to signal transduction and/or cardiovascular disease. Methods of determining susceptibility to morbidity and/or increased or early mortality are also described.
U.S. Pat. No. 6,107,104 (ICOS) relates to compositions and methods useful for isolating calcineurin as well as inhibiting calcineurin activity. The compositions are peptides that contain regions that are homologous to calcineurin-binding regions of Akap79. Also provided are methods for determining if a cell contains a calcineurin-binding and PKA-binding anchoring protein that are useful for identifying additional proteins that bind both calcineurin and PKA. Another aspect of the present invention is methods for enhancing expression of interleukin 2 by T cells. Further provided are methods to identify proteins which interact with AKAP79, and methods to identify inhibitors of AKAP 79 interaction with other proteins.
PCT/EP2013/060263 (WO2013/171332) discloses tri-alkyl(hetero)aryl amines which interfere with the ability of the A-kinase anchor protein (AKAP) 18δ to bind to the PKA substrate phospholamban. The compounds find use in treatment of cardiac disorders, especially cardiac failure.